Macrophages as Key Drivers of Cancer Progression and Metastasis

Figure 1

Prometastatic functions of macrophages. Macrophages promote invasion and intravasation of tumour cells at the primary site (purple). Tumour cells produce CSF1 that induces EGF expression in TAMs. This autocrine loop leads to comigration of tumour cells and macrophages towards blood vessels where macrophages produce VEGF-A to promote increased vessel permeability. In addition macrophage-derived molecules such as SPARC, CCL18, and proteases promote increased tumour cell invasion and migration. At the metastatic site, tumour cell-derived CCL2 recruits inflammatory monocytes to the metastatic site, where they differentiate into metastasis-associated macrophages that produce VEGF-A and cathepsin S to promote cancer cell extravasation. Macrophages promote survival at the metastatic site (green). Macrophages express integrin α4 that engages VCAM1 on tumour cells at the metastatic site, which increases tumour cell survival through PI3K/Akt signalling. In addition, macrophages bind to fibrin complexes on tumour cell-associated platelets, which increase tumour cell survival in the initial phase of metastatic colonisation. Macrophages promote metastatic niche formation (pink). Metastasis-associated macrophages produce granulin that activates HSTC to produce ECM molecules, such as collagen and periostin, which enhances the colony formation abilities of cancer cells in the metastatic niche of pancreatic cancer. In addition, tumour-derived exosomes can activate TGFβ expression in Kupffer cells that activates HSTCs to produce fibronectin in the premetastatic liver. Macrophages promote therapeutic resistance (blue). Macrophages produce IL-10 that inhibits the effector functions of CD8+ T cells by blocking the effects of dendritic cell-derived IL-12. Inhibition of IL-10 with a blocking antibody in combination with chemotherapy improves the therapeutic response. Tumour cells express CXCL1/2 that induces S100A8/9 production in macrophages to improve tumour cell survival. Chemotherapy induces TNFα expression from cancer-associated fibroblasts and endothelial cells that reinforces the CXCL1/2-S100A8/9 axis and limits the efficacy of chemotherapy.